Inflammation is the foundation for cancer and degenerative/autoimmune diseases. Small changes in diet and exercise, e.g. omega-3 oils, vitamin D, low starch, and maintaining muscle mass, can dramatically alter predisposition to disease and aging, and minimize the negative impact of genetic risks. Based on my experience in biological research, I am trying to explain how the anti-inflammatory diet and lifestyle combat disease. 190 more articles at http://coolinginflammation.blogspot.com

Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:

Monday, August 29, 2011

Naltrexone can be used to block opioids and provide the basis for treatment for drug abuse, but in low doses (LDN) it provides a paradoxical increase in natural endorphins that reverses inflammation and provides an effective treatment for autoimmune diseases, e.g. MS.

Receptors
A recent anonymous post brought the role of cannabinoid and opioid receptors in baldness to my attention. The relationship between these receptors, inflammation and autoimmunity is very complex. The heat and cold sensors, which also bind capsaicin and menthol, appear to be mediated by endorphins. Acupuncture also seems to function by similar mechanisms and is inhibited by high dose Naltrexone.

Low Dose Naltrexone
A side effect of high dose Naltrexone (e.g. 50 mg/d) is hair loss. Low dose Naltrexone (e.g. 1 mg/day, taken at night) appears to stimulate hair production and it may reverse the effects of Finasteride, since LDN improves libido.

Endorphin-Suppressed Inflammation
I would expect hair loss to be prevented/reversed by topical treatments that block inflammation and autoimmune attack on hair follicles. Curcumin, from turmeric, blocks NFkB and appears to help hair loss. Capsaicin can block inflammation via endorphin production and also helps hair loss. I would also expect that topical menthol and castor oil would reduce hair loss.

Anti-Inflammatory Diet
The anti-inflammatory diet that I recommend, may not be sufficient to block hair loss, but it may provide a good foundation for other anti-inflammatory treatments. In fact, other topical treatments may not be effective unless chronic, diet-based inflammation is eliminated. It may also be important to reduce oxidative stress by optimizing glutathione and vitamin C.

I would appreciate comments by others who may have experience with LDN and balding.

Tuesday, July 19, 2011

Male pattern baldness appears to result from the interaction between enzyme-modified male sex hormones (DHT) and receptors in some hair follicles of the scalp. Inhibition of the enzyme by topical (Rogaine) or oral administration (Propecia) of an inhibitor, e.g Finasteride, can stop hair loss. One of the significant side effects of oral use of Finasteride is loss of all sexual functions, which can be temporary and reversible after the drug is stopped, or permanent. I think that inflammation may play a critical role in both hair loss (and prostatitis) and loss of sexual functions in response to Finasteride and an anti-inflammatory approach my be helpful.

Testosterone is Converted to Dihydrotestosterone (DHT) by 5-Alpha Reductase

The male hormone, testosterone, is produced in the testes and travels to hair follicle or to other parts of the body via the blood in either a free state, or bound to a carrier protein. Only the free form interacts with the 5-alpha reductase enzyme in the scalp to produce the DHT that diminishes hair follicles. Application of the Reductase inhibitor, Finasteride, directly to the scalp stops the production of DHT in the scalp. Taking oral Finasteride blocks DHT production throughout the body, and unlike topical application, can also result in apparent changes in the brain, which can explain loss of sexual behavior.

DHT Role in Hair Loss and Brain-Based Sexual Behavior is Poorly Understood

Surprisingly, the molecular biology of male pattern baldness (MPB) is not known, even though this is one of the classic examples of a dominant, sex-associated phenotype, i.e. a single copy of the baldness allele in males produces baldness. Of course, this is not a sex linked gene, since baldness is not inherited from mothers with their X chromosome, and in some cases as many as 80% of the males in a single family exhibit male pattern baldness. It appears to me that baldness is also likely to have an environmental, e.g. gut flora, heritability similar to obesity. In fact, metabolic syndrome and type 2 diabetes are substantial risk factors for male pattern baldness.

There is also an association between MPB and polycystic ovary syndrome (PCOS) in females of the same family. I would also expect that MPB is related to prostatitis, since the prostate is a major processor of testosterone to DHT via 5-alpha reductase and prostatitis can be treated with Finasteride. PCOS is also treated with Finasteride. PCOS is also associated with obesity and metabolic syndrome. Prostatitis, PCOS, obesity and metabolic syndrome can all be treated as inflammatory diseases with significant contribution of dysfunction of gut flora.

PMB, Testosterone, 5-Alpha Reductase and Aromatase

In PMB, testosterone levels are lower and 5-alpha reductase is higher. This suggests that testosterone has been converted into DHT in scalp hair follicles. In order for DHT levels to make a difference, the hair follicles have to have specific receptors for DHT. Testosterone/DHT receptors, like all steroid hormone receptors, are proteins in the cytoplasm of cells, which bind the hormone and become activated as transcription factors that migrate to the nucleus and control the expression of particular genes.

Testosterone can also be converted by another enzyme, aromatase, into estrogen. DHT cannot be converted enzymatically into estrogen. Estrogen has a separate receptor and controls a different set of genes. Thus, enhanced conversion of testosterone into DHT in MPB follicles, may shift the balance away from estrogenic in favor of androgenic effects. Women exposed to aromatase inhibitors, stop converting their limited testosterone into estrogen and more is converted into DHT, resulting in rapid signs of baldness. All brain estrogen is produced from testosterone via aromatase in the brain and aromatase inhibitors can reduce libido in women.

DHT Activates Inflammatory NFkB (and Block Nerve Apoptosis?)

Prolonged exposure of cerebral blood vessels to DHT has been shown to activate the inflammatory transcription factor NFkB. Conversion of testosterone to DHT by 5-alpha reductase may amplify the inflammatory impact of testosterone by virtue of the stronger activation of the androgen receptor by DHT. Activation of NFkB also suppresses apoptosis and may be necessary to maintain some neural cells. Reducing DHT production by 5-alpha reductase inhibitors, may reduce NFkB activation in the brain and expose androgen-sensitive parts of the brain to apoptosis. This loss of brain cells may result in loss of sexual behavior.

Vitamin D is also Steroid Hormone/Co-Transcription Factor

It should be remembered that vitamin D also has a cytoplasmic receptor that acts as a transcription factor and that vitamin D deficiency can result in hair loss. If fact, vitamin D is required for the normal hair growth cycle, as well as intestinal villi development (defensin production). The vitamin D receptor can also inhibit the inflammatory transcription factor NFkB.

Thus, multiple steroid hormone receptors are involved in hair development, prostate function and brain sexual behavior. Modification of the conversion of testosterone into DHT or estrogen can have diverse consequences directly or indirectly by modification of inflammation/development signaling. This is also true of fertility/menstrual cycles, mammary tissue and perhaps intestinal epithelial villi or skin/follicle development in the case of rosacea. All of these processes are affected by enzymatic interconversion of steroid hormones and interaction of hormone/receptor and NFkB transcription factors.

Questions

The questions that I have about hair loss (or prostatitis), treatment with 5-alpha reductase inhibitors, and subsequent loss of sexual function are:

Why are the genetics of MPB so unusual/non-Mendelian? There are too many males with MPB in the same family. This points to some hereditary predisposition, but with a major environmental component, e.g. “inherited gut flora.”

Why are only a few of the people treated with 5-alpha reductase inhibitors rendered permanently impotent?

There is anecdotal evidence that dexamethasone (or prostate message and antibiotics) can reverse some impotence. Does this indicate that inflammation is involved in hair loss and/or impotence? Where do the antibiotics act and is their action to kill bacteria?

Treatment for Finasteride-Induced Impotence

Impotence is a severe side effect of a few men using Finasteride to treat baldness or prostatitis. I doubt that those with induced impotence are genetically predisposed, but rather these individuals probably had an altered immune system. I suspect two types of alterations: a compromised blood/brain barrier and a compromised suppressive immune system. Diet-based chronic inflammation is a typical path to a leaky blood/brain barrier that facilitates the penetration of Finasteride into the brain to alter 5-alpha reductase in the DHT-responsive regions responsible for sexual function. I presume that the subsequent reduction of DHT also results in inflammation that contributes to loss of function. Dexamethasone and some antibiotics could attenuate the inflammation and return normal function.

Suppression of attack of normal tissues by the immune system is mediated by development of the suppressive immune system in the gut in response to specific bacteria of the gut flora. A history of antibiotic treatment can yield a dysfunctional gut flora and a compromised immune system that results in allergies and autoimmunity. Prostatitis may have an autoimmune component and may result from compromised gut flora.

All of the symptoms discussed from hair loss to prostatitis to impotence should be improved by normal function of the gut and immune system by my anti-inflammatory diet and normal gut flora. Use of antibiotics will always lead to further side effects by perturbing and limiting the function of gut flora and the immune system that is dependent on the gut flora.

I particularly suspect that vitamin D deficiency is a significant contributor. Most “anti-inflammatory diets” will lead to chronic inflammation, because they are just high carb diets with a few vegetables. All of the complex phytochemicals produced by plants will be “antioxidants”. Adding these antioxidants to an inflammatory diet has no impact. Look at my anti-inflammatory diet and note that it requires attention to serum vitamin D levels, gets most calories from saturated fat and not carbs (low carb/high saturated fat), no vegetable oils and high omega-3 (EPA, DHA) to 6 ratio. That means meat/fish/eggs/dairy and lots of fresh vegetables for new gut bacteria.

Saturday, July 2, 2011

Jimmy Moore invited me to speak on his Livin' La Vida Low Carb show. So I recorded a conversation with him about low carb diets, inflammation and disease. It was great fun to talk about fixing gut flora and the benefits of an anti-inflammatory diet that is based on low carbs and high saturated fats.

Wednesday, June 29, 2011

The human body only produces enzymes to digest proteins, fats, starch and a few simple sugars. The remaining components of food either pass through the intestines undigested (insoluble fiber) or are digested by bacteria and fungi in the colon (soluble fiber.) Soluble fiber feeds gut flora. Insoluble fiber is usually minimized by traditional food preparation, for example grains, because it contains unhealthy materials, such as phytic acid. Soluble fiber is healthy and required for normal development of the gut/immune system, whereas insoluble fiber should be avoided.

Soluble Fibers in Vegetables are Carbohydrates/Polysaccharides

Plant cells are surrounded by cell walls composed of long chains of sugars, polysaccharides. These wall polysaccharides, e.g. pectin, arabinogalactans, xyloglucans, and storage glucans and fructans, are highly complex in structure and can only be digested down to simple sugars by the action of dozens of different enzymes produced by dozens of different bacterial species in the colon. Many plants (as well as fungi and bacteria) also produce unique polysaccharides that are only susceptible to additional unique bacteria enzymes. Thus, digestion of diverse vegetables requires hundreds of different species of bacteria in the gut. Healthy gut flora consists of more than 150 different species of bacteria, which were eaten with food and adapt to the gut environment.

Enzymatic treatment of complex polysaccharides in the gut is a complex process that also yields many intermediate products that can influence both gut flora and the gut itself. A well adapted gut flora can systematically digest most of the food molecules that pass into the colon and produce only short chain fatty acids (CFAs) that feed the colon and pass through the liver to the rest of the body.

Antibiotics or a history of limited food choices and excessive hygiene can result in a simplified gut flora that only partially digests soluble fiber and results in accumulation of unusual byproducts that irritate the gut, and cause bloating and gas. Adverse reactions are called food intolerances or food allergies. Since bowel stools are composed predominantly of loosely packed gut flora, inability to fully digest and convert soluble fiber into more gut flora, also results in constipation.

Soluble Fiber in Meat is also Polysaccharide

Meat is made of fibers of protein connected to bone by polysaccharides. The tendons, gristle and other chewy parts of meat are made of chondroitin sulfate and other glycosaminoglycans (GAGs). Heparin is another GAG, which is released onto the surface of the intestines to block the adhesion of viruses and pathogens to the gut, and is subsequently digested by colon bacteria. Other components of meat (and vegetables), such as nucleic acids and some fats are also digested by enzymes of the gut flora. The versatility of gut flora to adapt to a huge variety of foods permits people to live on very diverse diets, ranging from vegan to paleo.

Modern Diets Starve and Simplify Gut Flora

Modern diets consist of processed foods that are made of fat, protein and starch, all of which are digested and absorbed before reaching the colon. These simplified foods produce a simplified gut flora that may also produce more CFAs rather than stool forming gut bacteria. In other words, eating larger amounts of simpler foods can result in more of the nutrients being absorbed and making it easier to gain weight on less food with a tendency toward constipation. These diets may also select for bacteria that maintain the simplified, "efficient" gut flora community and provide the potential for the spread of obesity through a population. Having friends and relatives who are obese and presumably have gut bacteria that favor obesity, increases the risk of obesity. It seems likely that obesity is contagious.

Simplified Gut Flora also Means a Compromised Immune System

Complexity in the gut flora is also needed to produce a healthy immune system, because different species of bacteria in the gut stimulate the development of different parts of the immune system, which develop in the lining of the gut. Soluble fiber is the normal food for the colon bacteria that control the part of the immune system that regulates autoimmunity and allergy, for example. Obesity is also associated with increased risk of degenerative and autoimmune diseases, which is consistent with defects in the gut flora that reside in the colon. Thus, the modern high carb diet contributes to the symptoms of obesity by elevating blood sugar, blood CFAs, as well as compromising the gut flora needed for normal functioning of the immune system.

Healthy Gut Flora = Anti-Inflammatory Diet + Eating New Bacteria

A damaged or simplified gut flora can be fixed by eating foods that supply nutrients for the body as well as feeding the gut flora, e.g. plenty of different types of soluble fiber. It is also necessary to eat the missing bacteria. Just adding a few probiotics with yogurt will not fix the problem and cooking kills all of the good bacteria. Fermented foods, especially those based on bacteria from your own home and garden, are good sources of health-providing bacteria. Raw vegetables will also provide bacteria that may be useful in your gut flora, as long as the vegetables are not too thoroughly washed. Sterilizing and cooking vegetables may avoid rare pathogens, but will certainly prevent contributions to a healthy gut flora.

Tuesday, June 14, 2011

Healthy people don't get sick from food poisoning, because their gut flora provide protection. Gut bacteria control the development of the human immune system by producing interesting compounds, including short chain fatty acids and vitamins. In response to the gut bacteria, the healthy immune system produces white blood cells that can effectively attack bacteria, and also control this aggressive behavior to spare human cells and avoid unnecessary attacks on beneficial bacteria.

Disrupted Gut Flora Lead to Susceptibility to Disease/Infection

Gut flora can be compromised by what we eat and antibiotics. Those normally affected by food poisoning are the very young (on formula), the old (constipated) and those treated with antibiotics. Each of these groups have abnormal gut flora. Food poisoning is rarely observed in exclusively breastfed babies being introduced to foods, because human milk contains potent antimicrobial polysaccharides (human milk oligosaccharides) that only permit the growth of a few species of Bifidobacteria. Formula (in any amount) disrupts the normal development of the gut and immune system by stimulating an inflammatory growth of adult gut bacteria, making these babies more susceptible to intestinal and respiratory diseases, including food poisoning.

Constipation, which is more common in older people, reflects a disruption of the gut flora and decreases the effectiveness of the immune system in these individuals. In most cases the compromised gut flora results from a long history of a restricted diet and reduced access to environmental sources of bacteria.

Antibiotics are usually ignored as major corruptors of the immune system, even though they are known to produce diarrhea and constipation. Doctors reluctantly suggest that people taking antibiotics should just eat some yogurt. This is a silly oversight that severely compromises future health, because probiotics supply only a tiny fraction of the 150 different species of bacteria needed for a healthy body and immune system.

Pathogenic E. coli is Made by Antibiotic Use in Cattle

E. coli is a common and essential resident of the human gut and the best studied bacterium. This bacterium is not normally resistant to antibiotics nor does it produce deadly toxins. Antibiotic resistance and toxin production results from treating cattle with antibiotics to increase fat production prior to butchering.

Antibiotics Select for E. coli that Stick to Rectal Surface of Cattle

Pathogenic E. coli are not found throughout cattle fecal material, but rather they are only in the outermost surface layer. This outer layer of material contains bacteria from the surface of the rectum just as the cow pies are deposited. E. coli does not normally stick to this surface, because it lacks a protein, such as a hemagglutinin capable of binding to the surface polysaccharides, heparan sulfate. Antibiotics kill off the bacteria normally residing on the surface. As a member of the intestinal biofilm community, E. coli continually exchanges DNA/genes with other bacteria in the gut and picks up three useful genes, to become a pathogen:

Antibiotic resistance

Hemagglutinin for sticking to surfaces

Toxin to release nutrients from the intestinal walls.

E. coli with these three genes can colonize the rectal tissue of cattle in feed lots.

Pathogenic E. coli Can be Easily Avoided

We have to work hard as a society to have problems with E. coli. Pathogenic E. coli results from absurd use of huge quantities of antibiotics just to disrupt the normal gut flora of cattle so that they become unhealthy and store fat in their tissues, i.e. prime beef. The same effect can also be achieved just by feeding the cattle some short chain fatty acids, or better still avoiding this step by feeding exclusively on grass. It would also be easy to treat the few cattle that have pathogenic E. coli, so that it doesn't become a problem. Proper treatment of manure and meat processing would also block transmission of pathogenic E. coli to agricultural crops or meat. Finally, an Anti-inflammatory Diet and Lifestyle would provide a healthy gut flora and immune system that would make people less susceptible to the pathogen.

Thursday, June 9, 2011

Recent articles in the popular press have heralded the genetic engineering of cows with some human milk proteins. Milk produced by these transgenic cows is advertised as being similar or the same as human breast milk.

This is like claiming that the udder in the picture is an all natural, low BPA container for fortified water.

The breakthrough in humanized cow's milk, announced by Chinese researchers in PLoS One, actually documents replacement of cow lysozyme with the corresponding human enzyme. That does not make the milk human anymore than adding egg white lysozyme would turn the cows into chickens. If it moos like a cow...

Cow's milk-based formula harms infants, because the carbohydrates it contains do not support the normal development of infant gut flora. The result is gut inflammation, and not normal gut and immune system development. Even human proteins produced in cows will have characteristic cow sugars attached. It is these cow sugars on milk proteins that are associated with colic. The chains of sugars (milk oligosaccharides) free and/or associated with milk proteins are different in cows and humans, and cow carbs are a problem in formula.

I think that it is silly to support humanizing cow's milk formula, when the sensible solution is to support breast feeding and licensed human milk banks. The natural approach is much cheaper and far healthier. Only human milk and human milk-derived fortifiers should be used for infants (especially preterm) in hospitals. It is time for the healthcare industry to realize that disruption of gut flora by antibiotics or artificial formula is a health risk. The data are clear -- cow's milk (including transgenic cow’s milk) in the hospital may be profitable, but it is unhealthy, e. g. contributes to Clostridiumdifficile and necrotizing enterocolitis infections, and contributes to long term health problems, such as inflammatory and autoimmune diseases.

Wednesday, June 1, 2011

Healthy gut flora: bacteria from family, friends, Fido and food provide the foundation for the complex microbial community of the intestines, which controls the immune system. Antibiotics and hygiene are detrimental to gut flora and health.

Gut Flora Are Complex

Recent studies of the gut flora, e.g. the human gut biome, show that each individual maintains more than 150 different species of bacteria. Worldwide, that means that about a thousand different bacterial species are common residents of the human gut and together those gut bacteria use more than 1 million different genes. Many of those genes code for the enzymes used by gut bacteria to digest plant polysaccharides, i.e. soluble fiber.

Hygiene Isolates People from Healthy Sources of Gut Flora

Every time we speak, we release a mist of bacteria from our lungs, mouth and GI tract. These bacteria are on our skin, clothes and personal items, and provide a source of the bacteria that make us healthy. Parents and older siblings pass these bacteria on to younger children. These donated bacteria are essential for the development of a healthy immune system and children growing up with healthy relatives and exposed to soil bacteria via pets, farm animals, etc. are healthier than children who are more isolated.

In this sense, hygiene is unhealthy, because an individual is isolated from new sources of bacteria that could replace those lost by limited diets, antibiotics, etc. Otherwise, health is contagious, since gut bacteria from healthy individuals can spread among the population. Washing hands and food is unnatural and unhealthy.

Few Bacteria Make You Sick, but Many Are Essential for Good Health

Food intolerance can result from “good” family hygiene, limited diets and exposure to antibiotics. A common intolerance results from the absence of bacteria that produce an enzyme to digest dairy lactose, i.e. lactose intolerance. Lactose intolerance can be readily cured by eating a dairy product, such as yogurt, that contains both lactose and live bacteria (probiotics) that can digest the lactose. Simply eating moderate amounts of live yogurt daily for a couple of weeks resupplies the gut flora with bacteria that can digest lactose, and the intolerance is gone.

Soluble Fibers Are Plant Polysaccharides that Are Digestible by Bacterial Enzymes

Humans only produce enzymes to digest one polysaccharide, starch. All of the other hundreds of polysaccharides present in plants are only digestible by bacterial (and fungal) enzymes of the gut flora. If the bacteria and enzymes needed to fully digest a particular food polysaccharide are absent, then digestive problems ensue and the polysaccharide can act as a laxative. Continual eating of the problem food with a new source of diverse bacteria, e.g. lightly rinsed vegetables right from the garden, then the gut flora will incorporate new bacteria that can digest the problem polysaccharide and the gut is happy.

Soluble fiber feeds the gut bacteria that convert it into short chain fatty acids that nourish the colon. Constipation results from the absence of the bacteria needed to digest dietary fiber and to produce the large volume of bacteria that make up well hydrated stools.

Gut Bacteria Are Needed for Healthy Immunity

Cells of the human immune system are stored predominantly in the lining of the intestines. Intensive study of the interaction of the gut bacteria with the gut has revealed that both the aggressive half of the immune system that attacks pathogens and the suppressive half that protects the body itself from attack, develop in the gut in response to particular types of bacteria. Thus, the absence of one type of bacteria can cripple responses to infection, while other bacteria are needed to block autoimmune diseases and allergies. Most diseases are caused by disruption of the normal interactions between gut bacteria and the immune cells developing in the gut.

Antibiotics Lead to Autoimmunity

Antibiotics have dramatic and lasting impact on gut flora. Cattle treated with antibiotics and a high carbohydrate diet have an altered metabolism (obesity) that leads to rapid fat accumulation in their tissues. This is good for making tasty beef, but the same approach in people produces the suite of diseases in affluent societies.

Children treated with an antibiotic for a simple ear infection, are much more likely to return to pediatricians for treatments of subsequent obesity, infections and diseases. Compromised gut flora can take years to return to normal function after antibiotic treatment. Loss of the appendix, which is the normal source of bacteria to replenish gut flora after diarrhea, results in an increased risk of abnormal gut flora and numerous autoimmune diseases. It is likely that most autoimmune diseases are preceded by prior treatment with antibiotics that disrupted normal gut flora and permanently altered the immune system.

Interventions to Treat Disease: the Anti-Inflammatory Diet and Fecal Transplants

It should be obvious that a disrupted or unhealthy gut flora will compromise the immune system and contribute to disease. Treatment of diseases is complicated by the use of drugs that also impact the gut flora and produce additional side effects. An alternative approach would be to support the healthy gut flora and normal development of the gut immune system. As always, the answer is a supportive diet and a source of gut bacteria. The diet is obviously the Anti-Inflammatory Diet that provides support for almost anything that ails you. Probiotics are not retained in the gut, but they can contribute a few of the genes needed for a healthy gut flora. The source of bacteria for a healthy gut flora may range from minimally washed garden vegetables, to the more aggressive total replacement of gut flora with a fecal transplant from a healthy donor.

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About Me

I grew up in San Diego and did my PhD in Molecular, Cellular and Developmental Biology (U. Colo. Boulder). I subsequently held postdoctoral research positions at the Swedish Forest Products Research Laboratories, Stockholm, U. Missouri -Colombia and Kansas State U. I was an assistant professor in the Cell and Developmental Biology Department at Harvard University, and an associate professor and Director of the Genetic Engineering Program at Cedar Crest College in Allentown, PA. I joined the faculty at the College of Idaho in 1991 and in 1997-98 I spent a six-month sabbatical at the National University of Singapore. Most recently I have focused on the role of heparin in inflammation and disease.